Holosymmetric biphenyl derivative, and preparation method therefor and use thereof

Abstract

A holosymmetric biphenyl derivative and a preparation method therefor and the use thereof are described. Particularly provided are a holosymmetric biphenyl derivative having the structure of formula (I), and a preparation method therefor and a pharmaceutical composition containing same. The series of compounds can be widely used for the preparation of a drug for preventing and/or treating PD-1/PD-L1 signal pathway-mediated cancers or tumors, immune-related diseases and disorders, communicable diseases, infectious diseases or metabolic diseases, and are expected to be developed into a new generation of PD-1/PD-L1 inhibitors.

1 . A compound of formula (I), a stereoisomer or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein, both R 1  are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-4  alkyl and C 3-6  cycloalkyl, the C 1-4  alkyl and C 3-6  cycloalkyl are further optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  deuterioalkyl, cyclopropyl, hydroxy and C 1-4  alkoxy; 
         both R 2  are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, C 1-4  alkyl, C 3-6  cycloalkyl and hydroxy, the C 1-4  alkyl and C 3-6  cycloalkyl are further optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  deuterioalkyl, cyclopropyl, hydroxy and C 1-4  alkoxy; 
         both R 3  are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, C 1-10  alkyl, C 3-10  cycloalkyl and 3-10 membered heterocyclyl, the C 1-10  alkyl, C 3-10  cycloalkyl and 3-10 membered heterocyclyl are further optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxyl, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  deuterioalkyl, C 3-6  cycloalkyl, 3-6 membered heterocyclyl, C 6-10  aryl, 5-8 membered heteroaryl, C 3-6  cycloalkoxy, 3-6 membered heterocycloxy and C 1-4  alkoxy; 
         both m are identical or different and are each independently 0, 1, 2, 3 or 4; 
         both n are identical or different and are each independently 0, 1, 2, 3 or 4. 
       
     
     
         2 . The compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof of  claim 1 , wherein both R 1  are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  deuterioalkyl, cyclopropyl-substituted C 1-4  alkyl and C 3-6  cycloalkyl;
 preferably, both R 1  are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, cyclopropylmethyl and cyclopropyl.   
     
     
         3 . The compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof of  claim 1 , wherein both R 2  are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  deuterioalkyl, cyclopropyl-substituted C 1-4  alkyl, C 3-6  cycloalkyl and hydroxy;
 preferably, both R 2  are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, cyclopropylmethyl, cyclopropyl and hydroxy.   
     
     
         4 . The compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof of  claim 1 , wherein both R 3  are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, C 1-4  alkyl, C 3-6  cycloalkyl and 3-6 membered heterocyclyl, the C 1-4  alkyl, C 3-6  cycloalkyl and 3-6 membered heterocyclyl are further optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxyl, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  deuterioalkyl, C 3-6  cycloalkyl, 3-6 membered heterocyclyl, C 3-6  cycloalkoxy and C 1-4  alkoxy;
 preferably, both R 3  are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, oxacyclobutyl and azacyclobutyl, the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxacyclobutyl and azacyclobutyl are further optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxyl, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, cyclopropyl, cyclobutyl, oxacyclobutyl, azacyclobutyl, cyclopropyloxy, cyclobutyloxy, methoxy, ethoxy and isopropoxy;   more preferably, both R 3  are identical or different and are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, oxacyclobutyl and azacyclobutyl.   
     
     
         5 . The compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof of  claim 1 , wherein both R 1  are identical and are selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, cyclopropylmethyl and cyclopropyl;
 both R 2  are identical and are selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, cyclopropylmethyl, cyclopropyl and hydroxy;   both R 3  are identical and are selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, oxacyclobutyl and azacyclobutyl;   both m are identical and are 0, 1 or 2;   both n are identical and are 1 or 2.   
     
     
         6 . The compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof of  claim 1 , wherein the compound is selected from the group consisting of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A pharmaceutical composition, comprising the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         8 . A method for treating a PD-1/PD-L1 signal pathway-mediated disease comprising administering to a subject in need thereof the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof of  claim 1 . 
     
     
         9 . The method of  claim 8 , wherein the PD-1/PD-L1 signal pathway-mediated disease is cancer or tumor, immune-related disease and disorder, communicable disease, infectious disease or metabolic disease. 
     
     
         10 . The method of  claim 9 , wherein the cancer or tumor is lymphoma (including but not limited to lymphocytic lymphoma, primary central nervous system lymphoma, T cell lymphoma, diffuse large B cell lymphoma, follicle center lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma or primary mediastinal large B cell lymphoma), sarcoma (including but not limited to Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, angiosarcoma or lymphangiosarcoma), melanoma, glioblastoma, synovioma, meningioma, biliary tract tumor, thymic tumor, neuroma, seminoma, nephroblastoma, pleomorphic adenoma, hepatocellular papilloma, renal tubule adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, fibroma, central nervous system tumor, rhachiophyma, brain stem glioma, pituitary adenoma, multiple myeloma, ovarian tumor, myelodysplastic syndrome or mesothelioma, prostate cancer, recurrent prostate cancer or prostate cancer having developed resistance to existing medicaments, thyroid cancer, parathyroid cancer, anal cancer, testicular cancer, urethral carcinoma, penile cancer, bladder cancer, ureteral cancer, uterine cancer, ovarian cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, adrenal cancer, Merkel cell carcinoma, embryonal carcinoma, chronic or acute leukemia (including but not limited to acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic granulocytic leukemia and chronic lymphoblastic leukemia), bronchial carcinoma, esophageal cancer, nasopharyngeal carcinoma, hepatocellular carcinoma, renal cell carcinoma, small cell lung cancer, basal cell carcinoma, lung cancer, breast cancer, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, rectal cancer, colon cancer, colorectal cancer, gastric cancer, pancreatic cancer, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal cancer, bone cancer, skin cancer, small intestine cancer, endocrine cancer, renal pelvic carcinoma, epidermoid carcinoma, abdominal wall carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma or metastatic tumor;
 the immune-related disease and disorder is rheumatic arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemia, fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, systemic sclerosis or multiple sclerosis;   the infectious disease is bacterial infectious disease, viral infectious disease or fungal infectious disease;   the communicable disease or infectious disease is sepsis, liver infection, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, papillomavirus or influenza;   the metabolic disease is diabetes, diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome, hypoglycemia, gout, malnutrition, vitamin A deficiency, scurvy, vitamin D deficiency or osteoporosis.   
     
     
         11 . (canceled)